Is GPHN p.Arg34His (c.101G>A) pathogenic?

GPHN p.Arg34His (c.101G>A) is classified Uncertain significance in GPHN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: ambiguous (0.3987); Very rare (popmax 0.00224%, eas); Associated with sulfite oxidase deficiency due to molybdenum cofactor deficiency type C.

What condition is associated with GPHN p.Arg34His (c.101G>A)?

GPHN p.Arg34His (c.101G>A) is associated with sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (ClinVar).

How common is GPHN p.Arg34His (c.101G>A) in the general population?

GPHN p.Arg34His (c.101G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about GPHN p.Arg34His (c.101G>A)?

AlphaMissense predicts ambiguous (score 0.3987) — an in-silico prediction, not a clinical call.

GPHN p.Arg34His

c.101G>A · VCV3728066

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Conditions

sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

Computational evidence

Protein change
AlphaMissense	0.3987	ambiguous
REVEL	0.576	indeterminate
SaProt	LLR -12.75	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 316 kb · p 0.99 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,700 alleles

Filtering AF 0.000433% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000316%

Overall 0.000875% 14/1,599,356 alleles · very rare exomes 13/1,447,224 · genomes 1/152,132 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,700
Remaining individualsnot grpmax-eligible	0.00161%	61,976
African / African-American	0.00134%	74,544
South Asian	0.0011%	90,724
European (non-Finnish)	0.000856%	116,793

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GPHN
Protein: p.Arg34His
Coding: c.101G>A
MANE Select: NM_020806
Type: single nucleotide variant
Location: chr14:66681143 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 84.15 · 1 PDB
Residue 34: the 'mpt mo-transferase' region; an α-helix

Full GPHN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sulfite oxidase deficiency due to molybdenum cofactor deficiency type C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GPHN p.Arg34Cys Uncertain significance ★★ ⚠ same residue
VTI1B p.Gly34= Benign ★★ same residue
RDH12 p.Asn34His Uncertain significance ★ ⚠ same residue
RDH12 p.Asn34= Likely benign ★ same residue
GPHN c.828+1G>A Likely pathogenic ★★ same condition
GPHN p.Tyr56Ter Pathogenic/Likely pathogenic ★★ same condition
GPHN c.1413+3A>G Uncertain significance ★★ same condition
GPHN p.Ala239Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gphn-p-arg34his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown